tbuckley/cabot-search huggingface dataset:
Abstract 11939: Phosphorylation of Serca2 at Serine 663, a Physiological and Clinical Event in Ischemic Heart Diseases, That Regulates Intracellular Ca <sup>2+</sup> and Cell Death
Authors: FABRICE GONNOT, Maya Dia, Yves GOURIOU, Gabriel Bidaux, Christophe Chouabe, Claire Crola Da Silva, Sylvie Ducreux, Bruno PILLOT, Andrea Kaczmarczyk, Christelle Leon, Coralie Perret, Franck Sciandra, Fadi Farhat, laurent Sebbag, Thomas Bochaton, Helene Thibault, Michel Ovize, Melanie Paillard, Ludovic Gomez
Journal: Circulation (2022)

Introduction: Despite advances in cardioprotection, new therapeutic strategies capable of preventing acute myocardial ischemia-reperfusion injury and reducing secondary event of patients are still needed. Hypothesis: We hypothesized that limitation of SERCA2 phosphorylation on a serine/threonine residue at reperfusion could provide protection against reperfusion injury, via the activation of the Ca 2+ reuptake into SR/ER which confers detoxification of the cytosolic and mitochondrial Ca 2+ overload during reperfusion . Methods: Combining in silico analysis with in vitro and in vivo genetic approaches, we discovered that the phosphorylation of SERCA2 at serine 663 is a clinical and pathophysiological event of cardiac function. Results: We demonstrated that the phosphorylation level of SERCA2 at serine 663 is increased with heart damage in both patient and mouse ischemic hearts. Mechanistically, we demonstrated that preventing serine 663 phosphorylation significantly increased SERCA2 Ca 2+ pumping activity into the reticulum and protected against hypoxia/reoxygenation-induced cell death, by counteracting the cytosolic and mitochondrial Ca 2+ overload. To link this specific residue event to a physiological role of SERCA2 in heart, we demonstrated that gene therapy for the phosphoresistant form of SERCA2 at serine 663 improved the excitation/contraction coupling of cardiomyocytes and significantly reduced infarct size in an in vivo myocardial infarction model, whereas mice expressing a phosphomimetic form of SERCA2 developed a larger infarct size. Conclusions: Together, these findings establish the pathophysiological role and the therapeutic potential of SERCA2 modulation in acute myocardial infarction, based on the hotspot phosphorylation level of SERCA2 on its serine 663 residue.
Abstract 11892: Novel Measures of Arterial Stiffness and Wave Reflections Associate With Clinical Outcomes in Patients With Heart Failure
Authors: Rebecca Steinberg, Eisha Udeshi, Neal W Dickert, Arshed A Quyyumi, Julio A Chirinos, Alanna A Morris
Journal: Circulation (2022)

Introduction: Arterial stiffness and earlier wave reflections can increase afterload and impair cardiovascular function. Most prior studies have been performed in patients with preserved left ventricular (LV) function. Hypothesis: Novel measures of pulsatile arterial hemodynamics are predictive of worse clinical outcomes in patients with HFrEF. Methods: Patients with HFrEF (N=137, median age 56, 49% female, 58% Black) and age-matched healthy controls (N=124) underwent measurements of large artery stiffness and pulsatile arterial hemodynamics from 2015-2019 at a single study visit. Carotid-femoral pulse wave velocity (CF-PWV) and augmentation index (AIx) were assessed using high-fidelity applanation tonometry. In HFrEF patients, pressure-flow analyses were performed to derive aortic characteristic impedance (QZc), reflected wave transit time (RWTT), and wasted pressure effort (WPE). In HFrEF patients, Cox proportional hazards models examined associations between vascular function measures and 1) all-cause death and 2) a combined endpoint of left ventricular assist device (LVAD) implant, heart transplant (HT), and death at 2 years adjusted for race, BNP, and MAGGIC risk score. Results: Compared to controls, patients with HFrEF had similar CF-PWV (6.8+/-1.6 v. 7.0+/-1.6 m/s, P=0.4), and higher AIx normalized to a HR of 75 bpm (13+/-2% v. 22+/-2%, P&lt;0.001). Among HFrEF patients, a shorter RWTT was associated with death (adjusted hazard ratio [aHR] 0.60, 95% confidence interval [CI] 0.37-0.97) and the combined endpoint of death/LVAD/HT (aHR 0.62, 95% CI 0.41-0.94) at 2 years ( Figure ). WPE/QZc, which represents the proportion of systolic load from wave reflection, was associated with the combined endpoint on multivariable analysis (aHR 1.40, 95% CI 1.02-1.93). AIx and PWV were not predictive of clinical outcomes. Conclusion: Increased LV systolic load from premature wave reflections is associated with adverse clinical outcomes in patients with HFrEF.
Abstract 12449: Inhibition of the Sodium Potassium ATPase Alpha 3 (ATP1A3) Pump Function Alters Repolarization Time and is Proarrhythmic in Cardiac Myocytes
Authors: Scott Zheng, Minu-Tshyeto Bidzimou, Leonie Kurzlechner, ZHUSHAN ZHANG, Robin M Perelli, Mary E Moya-Mendez, Mohamad A Mikati, Andrew P Landstrom
Journal: Circulation (2022)

Introduction: Inhibition of Na + /K + -ATPase (NKA) is arrhythmogenic, but the specific effect of alpha 3 NKA isoform (ATP1A3) inhibition is unknown. Variants in human ATP1A3 can lead to ventricular arrhythmias, yet the mechanism remains unknown. Hypothesis: Loss of NKA function results in shortening of QT interval and increased arrhythmia susceptibility due to intracellular Na+ and Ca2+ overload. Pharmacological inhibition of sodium-calcium exchanger (NCX) can rescue ECG parameter changes and arrhythmic phenotypes by reducing Ca2+ overload in the cell. Methods: Whole-cell patch clamp action potential recordings were conducted on induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from an ostensibly healthy individual to measure action potential duration (APD) and presence of delayed after depolarizations (DADs). Cells were exposed to 10 -7 M ouabain and 10 -5 M ORM-10103 (a selective inhibitor of NCX). ECGs and in vivo intracardiac electrophysiology studies were performed in mice at 12-14 weeks of age after intraperitoneal drug administration of 5 μg/g ouabain and 10 μg/g ORM-10103. Results: APD recordings of iPSC-CMs demonstrated both shortening and lengthening of APD with ouabain exposure. In both models, DADs were found in 6 of 18 cells with ouabain treatment. These findings were rescued with pretreatment using ORM-10103, as 0 of 8 cells developed DADs. On mouse ECG recordings, ouabain led to QRS and QT prolongation. During programmed electrical stimulation, no arrhythmia was noted with vehicle-treated mice. Following ouabain administration, 2 in 12 mice developed induced monomorphic ventricular tachycardia. Pretreatment of ORM-10103 in mice did not rescue QRS and QT prolongation with ouabain administration. Conclusions: Pharmacologic inhibition of ATP1A3 variably altered cardiac repolarization time in a species-specific manner, yet was associated with a substrate for triggered arrhythmias. The arrhythmogenic phenotype was rescued with inhibition of NCX in human cardiac myocytes, suggesting that NCX plays a role in the arrhythmogenic mechanism of ATP1A3. However, these effects were not seen in murine cardiac myocytes. Exploration of specifies-specific differences in NKA isoform expression and cardiac repolarization is needed.
Abstract 11962: Cardiopulmonary Exercise Testing Predicts Mortality in Cardiac Amyloidosis: A Systematic Review and Meta-Analysis
Authors: Anna Cantone, Claudio Rapezzi, Piergiuseppe Agostoni, Federico Sanguettoli, Rita Pavasini, Daniele Maio, Luca Di Ienno, Gioele Fabbri, GABRIELE GUARDIGLI, Gianluca Campo, Matteo Serenelli
Journal: Circulation (2022)

Introduction: The cardiopulmonary exercise testing (CPET) has been proved to be a good tool in prognostic stratification of HFrEF and HFpEF, but its value in cardiac amyloidosis (CA) is uncertain. With the increasing knowledge and clinical suspicion toward CA, the growing prevalence of the disease, and the current availability of disease-modifying drugs, prognostic stratification is becoming fundamental to optimise the cost-effectiveness of treatment, patient follow-up and management. Hypothesis: We investigate the association of VO2max and VE/VCO2 slope with prognosis in patients with CA. Methods: We performed a systematic review following the PRISMA guidelines. Electronic databases (MEDLINE, Biomed Central, and Cochrane Library) were searched for clinical trials performing CPET for prognostication in transthyretin and light-chain CA patients. Studies reporting Hazard Ratio (HR) for mortality and VO2 max or VE/VCO2 slope (1-unit increase) were further selected for quantitative analysis. After logarithmic transformation, HRs were pooled using a random-effect model. Results: Five studies were selected for qualitative analysis and 3 for the quantitative analysis. A total of 233 patients were included in the meta-analysis, 127 (55%) with transthyretin and 106 (45%) with light-chain CA. Mean VO2 max in each trial was consistently depressed, ranging from a mean of 14.5 ± 4.5 mL/kg/min to 15.2 ± 10 mL/kg/min. On the other side, the VE/VCO2 slope ranged from a mean of 30 ± 3.0% to 41.3 ± 9.7%. Our pooled analysis shows that VO2 max (pooled HR 0.89, 95%CI 0.84-0.94) and VE/VCO2 slope (pooled HR 1.04, 95%CI 1.01-1.07) are significantly associated with the risk of death in CA patients, with no significant statistical heterogeneity for both analyses. Conclusions: CPET is a valuable tool for prognostic stratification in CA, identifying patients at increased risk of death. Large prospective clinical trials are needed to confirm this exploratory finding.
Abstract 11934: Natural Language Processing Models Can Be Trained to Accurately Recognize the Presence of Disease Within Clinical Notes
Authors: David Vidmar, Will Thompson, Ruijun Chen, Dustin Hartzel, Daniel Rocha, Joseph Leader, Brandon Fornwalt, Christopher M Haggerty
Journal: Circulation (2022)

Introduction: Automated methods to “label” the presence of disease such as atrial fibrillation (AF) within electronic health record (EHR) data are important for secondary uses such as population health management. Labels generated from billing code patterns (e.g. “at least 2 relevant ICD codes used within 1 year”) can be accurate within one health system, but may fail to generalize across systems due to variations in coding practices. Hypothesis: We hypothesized that a natural language processing (NLP) model could be trained to detect the presence of atrial fibrillation using unstructured clinical notes by learning at scale from labels generated from a validated structured EHR and billing code definition. If successful, this could facilitate scaling disease label methods across large amounts of clinical data without suffering from inaccuracies due to variations in coding practices. Methods: We collected clinical notes from a regional health system into a training set of roughly 29 million code-labeled episodes and a separate hold-out set of roughly 1.8 million code-labeled episodes. We trained our NLP model on the training set and computed model performance compared to the code-based labels on the hold-out set. We also performed targeted blinded chart reviews. This work was conducted under IRB approval. Results: The model achieved an AUPRC of 0.91 with 87% recall and 89% precision and learned to distinguish challenging confounders despite not being explicitly trained for these tasks (Fig). Blinded review of select episodes showed that the NLP model was correct 90% of the time when it labeled the episode as positive for atrial fibrillation despite the code-based label (incorrectly) labeling it negative. Conclusions: NLP models can learn to automatically label the presence or absence of atrial fibrillation within clinical notes and may lead to greater accuracy and generalizability relative to code-based labeling methods.
Abstract 12368: Results From the DoPING-HFpEF Trial: A Double Blind, Placebo-Controlled Randomized Cross-Over Trial Investigating Trimetazidine in Heart Failure With Preserved Ejection Fraction
Authors: Arno A Van De Bovenkamp, Adrianus J. J Bakermans, Kiki J Geurkink, Frank T Oosterveer, Frances S De Man, Wouter E Kok, Aart J Nederveen, Albert C van Rossum, M. Louis L Handoko
Journal: Circulation (2022)

Introduction: Due to mitochondrial dysfunction, cardiac energy homeostasis is compromised in heart failure with preserved ejection fraction. As left ventricular relaxation is an active and energy consuming process there is a clear relationship between the impaired cardiac metabolism and diastolic dysfunction. Here, we investigate whether trimetazidine, a fatty acid oxidation inhibitor, can improve cardiac energy homeostasis and consequently improve diastolic function. Methods: This was a single-center, double-blind, placebo-controlled randomized cross-over trial consisting of two treatment periods of three months with a 2 week washout period in between. Patients (N=25) were treated with 20mg trimetazidine or placebo t.i.d. or b.i.d. (based on kidney function). The primary endpoint was change in pulmonary capillary wedge pressure (PCWP) measured with right heart catheterization at multiple stages of exercise. Secondary endpoint was change in phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance (MR) spectroscopy. Results: All included patients had invasively proven heart failure with preserved ejection fraction. There was no effect on the primary outcome PCWP at multiple levels of exercise ( P =0.60). Myocardial PCr/ATP in the trimetazidine arm was similar to placebo ( P =0.08). There was no change by trimetazidine in the exploratory parameters 6-minute walking distance, NT-proBNP, overall quality of life, or other parameters for diastolic function measured with echocardiography and cardiac MR, or additional metabolic parameters. Trimetazidine plasma level are currently being assessed and will be available at the moment of presentation. Conclusion: Trimetazidine did not improve diastolic function or myocardial energy homeostasis in patients with HFpEF. Disclosure of unlabeled use: Trimetazidine was not labeled for use in HFpEF.
Abstract 12057: Absence of Pericarditis Recurrence in Rilonacept-Treated Patients With COVID-19 and mRNA Vaccinations: Experience From Phase 3 Rhapsody Long-Term Extension
Authors: antonio brucato, Lucia Trotta, Michael Arad, Paul C Cremer, Eliyazar Gaddam, Antonella Insalaco, Marc W Klutstein, Martin M Lewinter, David Lin, Sushil A Luis, Yishay Wasserstrum, Emily Plummer, Manoj Samant, Liangxing Zou, Allan L Klein, Massimo Imazio, John F Paolini
Journal: Circulation (2022)

Introduction: Rare cardiac complications of COVID-19 and COVID-19 mRNA vaccination include pericarditis and myocarditis. Patients with recurrent pericarditis may be at increased risk of triggered recurrence. The known efficacy of the interleukin (IL)-1 antagonist rilonacept in treating and preventing recurrence could inform COVID-19 disease and vaccination management. Methods: The Phase 3 trial RHAPSODY was a global, double-blind, placebo-controlled, randomized-withdrawal study. A long-term extension (LTE) enabled up to 24 months further open-label treatment from May 2020 until June 2022. Concomitant vaccination data and adverse events, including COVID-19, were collected. Results: No COVID-19 cases were reported during the run-in and randomized withdrawal periods (n=86). As of the 6 May 2022 data cutoff, a COVID-19 AE was reported in 19% (14/74) of LTE subjects, of whom 12 were on rilonacept: 5 of 44 fully-vaccinated (≥14 days beyond second serial dose) subjects (11.4%) and 9 of 30 unvaccinated or partially-vaccinated subjects (30.0%). Of the fully-vaccinated subjects, 1 case occurred ~11 months post primary vaccination cycle (no booster). COVID-19 severity was mild (n= 11), moderate (n=2), or severe (n=1). All cases resolved except the severe AE complicated by comorbidities; the subject discontinued. Of 12 subjects receiving rilonacept at the time of COVID-19 diagnosis, 10 maintained dosing with rilonacept, 1 interrupted rilonacept for ~4 weeks, and 1 discontinued rilonacept permanently; none experienced a pericarditis recurrence (PR) after the AE. The remaining 2 subjects had previously interrupted rilonacept for off-treatment observation: one had a PR &gt;4.5 months after suspending rilonacept and 18 days after COVID-19 resolution; no PR in the other (&gt;6 months). There were no PR AEs associated with COVID-19 vaccination (all subjects were receiving rilonacept). Conclusions: In patients on rilonacept in this study, although numbers are small, vaccination reduced COVID-19 events, pericarditis recurrence was not increased by vaccination or disease, and no pericarditis recurrences occurred during rilonacept treatment. One pericarditis recurrence occurred remotely after rilonacept suspension in the peri-COVID-19 period.
Abstract 11943: MCUF-651: A Novel Natriuretic Peptide Receptor A (NPRA) Small Molecule Positive Allosteric Modulator With Blood Pressure Lowering and Renal Enhancing Properties in Experimental Hypertension
Authors: Xiao Ma, Dante Moroni, Satyamaheshwar Peddibhotla, Xiaoyu Ma, Ye Zheng, Shuchong Pan, John C Burnett, Siobhan Malany, Jeson Sangaralingham
Journal: Circulation (2022)

Introduction: Hypertension (HTN) represents one of the greatest burdens in human health and is associated with increased morbidity and mortality. Despite the availability of several antihypertensive drugs, most patients have suboptimal blood pressure (BP) control, thus underscoring the need for new therapeutic drugs. The natriuretic peptide receptor A (NPRA) possesses potent vasodilating, natriuretic and diuretic actions via activation by ANP or BNP and generation of its second messenger, cGMP. Recently, we reported the discovery of a small molecule positive allosteric modulator (PAM) for NPRA, MCUF-651, which enhances the ANP/BNP/NPRA/cGMP pathway (PNAS,2021). To date, the in vivo actions of MCUF-651 remains unknown. Here we tested the hypothesis that MCUF-651 would have BP lowering and renal enhancing properties in experimental HTN. Methods: A single IV bolus of MCUF-651 (10mg/kg; n=4) or vehicle (V; n=5) was injected into anesthetized spontaneous hypertensive rats (SHRs). Plasma and urinary cGMP (PcGMP and UcGMP), mean arterial pressure (MAP) and urinary volume (UV) and sodium (UNa) excretion were assessed at baseline (BL) and over 60-mins post-bolus. Results: In SHRs, PcGMP and UcGMP were significantly elevated with MCUF-651 compared to the vehicle group (ΔPcGMP MCUF-651: 16±5, ΔPcGMP V: -2±3, pmol/mL; P =0.003; ΔUcGMP MCUF-651: 78±29, ΔUcGMP V: 30±8, pmol/min, P =0.01), thus supporting NPRA target engagement. Notably, the elevations in cGMP with MCUF-651 were associated with a significant reduction in MAP at 15-mins post bolus compared to vehicle (ΔMAP MCUF-651: -29±14, ΔMAP V: -6±2 mmHg; P =0.04) and this MAP reduction was sustained over 60 mins. Further, UV and UNa excretion were significantly increased, from BL, with MCUF-651 (BL UV: 6 ± 2, 60 mins post bolus UV: 56± 18 μL/min, P &lt;0.001; BL UNa: 1±0.2, 60 mins post bolus UNa: 8±2 μmol/min, P &lt;0.001). Conclusions: We report for the first time that MCUF-651, a novel NPRA small molecule PAM, engages NPRA, increases cGMP and reduces MAP while enhancing sodium and water excretion in experimental HTN. These findings support the development of MCUF-651 as a potential new therapeutic modality to optimize BP lowering goals and reduce adverse outcomes in human HTN.
Abstract 12051: Anticoagulation Use After Percutaneous Left Atrial Appendage Occlusion in Medicare Beneficiaries
Authors: Michael Blotner, Mohammed Ruzieh, Tianze Jiao, Nicole E Smolinski, Gerald Naccarelli, John M Mandrola, Andrew Foy
Journal: Circulation (2022)

Background: In the pivotal trials of percutaneous left atrial appendage occlusion (pLAAO), patients received warfarin for 45 days followed by dual antiplatelets up to 6 months post pLAAO; however, real-world use of anticoagulants post pLAAO implantation is unknown. Objectives: To assess prescription anticoagulation and antiplatelet use after pLAAO in Medicare beneficiaries. Methods: We used a 15% sample of Medicare claims data (2015-2018) to identify patients who received pLAAO. Prescriptions claims were used to assess anticoagulant and antiplatelet use (other than over the counter aspirin) up to 12 months post pLAAO. Results: A total of 2,780 patients were included. The mean CHA2DS2-VASc score was 4.9. There were 2,171 (78.1%) patients who were prescribed anticoagulants after pLAAO. The most common drug was warfarin (63.8% of total anticoagulants used), followed by apixaban in 23.2% of the patients. At 3 months, 54.3% of the patients were taking a potent antithrombotic (anticoagulant or a P2Y12 inhibitor) medication. The number of patients taking potent antithrombotics decreased over time but remained high at 6 months (40.9%) and at 12 months (19.0%). Conclusion: Anticoagulation use remained high at 6- and 12-months post pLAAO; longer than what’s used in the pivotal trials. Further studies are needed to determine if this is associated with increased bleeding risk. Furthermore, this data should be taken into consideration when assessing stroke risk post pLAAO.
Abstract 12163: Liver Disease in Right Heart Failure: Not Just Fontan Associated
Authors: Zane J Christmyer, Heidi Van, Clara Tow, Nadia Ovchinsky, Daphne T Hsu
Journal: Circulation (2022)

Introduction: Hepatic fibrosis, cirrhosis, and hepatocellular carcinoma caused by the Fontan circulation, known as Fontan Associated Liver Disease (FALD), are due to low cardiac output and high venous pressure within the Fontan circuit. Hypothesis: We hypothesized that patients with congenital heart disease causing right heart dysfunction would have liver findings similar to FALD. Methods: We identified patients with the Fontan circulation or congenital heart disease associated with moderately depressed or dilated RV on echo or MRI, and/or increased right atrial pressure on cardiac cath. We defined hepatic congestion as increased kPA on Fibroscan, liver or IVC abnormalities on US, increased kPA or liver abnormalities on MRI elastography, and/or sinusoidal congestion on liver biopsy. The incidence of hepatic congestion was compared by chi squared analysis. Results: A total of 33 patients were identified for this study, 23 Fontan and 10 non-Fontan. Hepatic congestion was found in 25 patients (76%). Hepatic congestion was most often diagnosed by US in both Fontan (82.6%) and non-Fontan patients (40%). The most common findings on liver biopsy, including one non-Fontan Ebstein, were sinusoidal dilation, portal fibrosis, and perisinusoidal fibrosis. The incidence of hepatic congestion in Fontan was no different from non-Fontan however power was limited. Conclusions: Hepatic congestion was found in 83% of Fontan and 60% of non-Fontan patients. Fontan and non-Fontan patients alike are at risk for hepatic congestion and there is need for further evaluation to understand the clinical relevance of hepatic congestion caused right heart dysfunction.